Recombinant adeno-associated virus (rAAV) vectors show great promise for gene therapy in a variety of different genetic disorders. AAV vectors have an excellent safety profile, as demonstrated in non-clinical and clinical studies. Furthermore, AAV vectors were shown to mediate a stable therapeutic transgene expression in several non-clinical studies, and more recently in clinical studies. AAV vectors have been successful in phase I/II studies for haemophilia B, cystic fibrosis, alpha-1 anti-trypsin deficiency, Parkinson disease, Duchenne muscular dystrophy and Leber's congenital amaurosis (Selot et al., Current Pharmaceutical Biotechnology, 2013, 14, 1072-1082). Alipogene tiparvovec (Glybera®, uniQure) has been granted marketing authorization in Europe as a gene therapy for the treatment of lipoprotein lipase deficiency (LPLD). Hence rAAV vectors are the gene transfer vectors of choice for the delivery of genes in humans in vivo.
One major challenge for a successful administration of AAV vector is the presence of neutralizing antibodies (immunoglobulins) (nAb) that have developed following exposure to wild-type AAV or AAV-based vectors. In both cases, the neutralizing serotype-specific antibodies directed towards the viral capsid proteins reduce the efficiency of gene transfer with AAV of the same serotype.
The current practice in the clinic with regard to pre-existing immunity involves the screening of patients for exclusion should patients have neutralizing antibodies against the AAV capsid (Brimble et al. Expert Opin Biol Ther 2016, 16(1):79-92 and Boutin et al. Hum Gene Ther 2010, 21:704-712). Immunosupressive regimens have been tried in order to reduce the formation of nAb upon first administration to allow for a second administration (Corti et al., Mol Ther—Meth Clin Dev (2014) 1, 14033; Mingozzi et al. Mol Ther vol. 20 no. 7, 1410-1416; McIntosh et al. Gene Ther 2012, 19, 78-85)).
Furthermore, strategies have been suggested to overcome pre-existing antibodies which include plasma exchange and the use of immunosuppressive regimens. Plasma exchange strategies involve the removal of plasma from the blood and exchanging it for plasma not containing neutralizing antibodies (e.g. from a donor or the subject itself) or a defined replacement fluid (Chicoine et al., Mol Ther 2014, vol. 22 no. 2 338-347; Hurlbut et al. Mol Ther 2010, vol. 18 no. 11 1983-1984). Immunosuppressive regimens aimed at reducing nAb include rituximab combined with Cyclosporin A (Mingozzi et al. Mol Ther vol. 20 no. 7, 1410-1416). Such strategies have been tested in animal models obtaining limited success, being somewhat effective in subjects having low nAb titers. In view of these results it has been suggested to combine different strategies and/or use a higher rAAV vector dose (tenfold) in order to overcome pre-existing antibodies and achieve effective transduction of e.g. the liver (Hurlbut et al. Mol Ther 2010, vol. 18 no. 11 1983-1984; Mingozzi et al. Mol Ther vol. 20 no. 7, 1410-1416).
Hence, there is a need in the art for strategies that allow administration of rAAV vectors in subjects that have, or may be suspected to have, neutralizing antibodies.